Composition and methods for the design and development of metallo-enzyme inhibitors

Abstract

The present disclosure provides compounds having the general structure A or pharmaceutically acceptable salts thereof: R—X  (A) wherein R is an alkyl or aryl moiety comprising heterocyclic structures; and X is a metal-chelatin group selected from: This disclosure further provides a focused library of compounds for use in the discovery and design of metallo-enzyme inhibitors. This fragment-based approach provides an assembly of a library of low molecular weight compounds (MW<300 Da) containing a variety of potential metal-chelating groups. The identification of the inhibitory scaffolds among these compounds provides the initial hit fragments that may be optimized for affinity against a particular target using common medicinal chemistry, structure-based or NMR-based approaches.

1 . A compound having the general structure A or a pharmaceutically acceptable salt thereof:
   R—X  (A)   wherein R is an alkyl or aryl moiety comprising heterocyclic structures; and   X is a metal chelating group among one of the following:   
     
       
         
         
             
             
         
       
     
   
   
       2 . A compound of  claim 1 , wherein the compound binds to a metallo-enzyme thus inhibiting its activity. 
   
   
       3 . A method of use of compounds A and derivatives from the general structure of  claim 1  as potent and selective metallo-enzyme inhibitors: 
   
   
       4 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 3  and a pharmaceutically acceptable carrier therefor. 
   
   
       5 . A method of treatment of human malignancies comprising administering a pharmacologically effective dose of a pharmaceutical composition of  claim 4  to a subject in need thereof, thereby treating and/or delaying the progression of the disease. 
   
   
       6 . A method of making a compound of  claim 1 , as shown in Examples 1, 2 or 3.